Journal of Computer-Aided Molecular Design

, Volume 15, Issue 7, pp 587–612 | Cite as

FLASHFLOOD: A 3D Field-based similarity search and alignment method for flexible molecules

  • Michael C. Pitman
  • Wolfgang K. Huber
  • Hans Horn
  • Andreas Krämer
  • Julia E. Rice
  • William C. Swope
Article

Abstract

A three-dimensional field-based similarity search and alignment method for flexible molecules is introduced. The conformational space of a flexible molecule is represented in terms of fragments and torsional angles of allowed conformations. A user-definable property field is used to compute features of fragment pairs. Features are generalizations of CoMMA descriptors (Silverman, B.D. and Platt, D.E., J. Med. Chem., 39 (1996) 2129.) that characterize local regions of the property field by its local moments. The features are invariant under coordinate system transformations. Features taken from a query molecule are used to form alignments with fragment pairs in the database. An assembly algorithm is then used to merge the fragment pairs into full structures, aligned to the query. Key to the method is the use of a context adaptive descriptor scaling procedure as the basis for similarity. This allows the user to tune the weights of the various feature components based on examples relevant to the particular context under investigation. The property fields may range from simple, phenomenological fields, to fields derived from quantum mechanical calculations. We apply the method to the dihydrofolate/methotrexate benchmark system, and show that when one injects relevant contextual information into the descriptor scaling procedure, better results are obtained more efficiently. We also show how the method works and include computer times for a query from a database that represents approximately 23 million conformers of seventeen flexible molecules.

context-adapted similarity measure drug design field-based similarity searching flexible alignment fragment assembly molecular fragmentation molecular property fields molecular similarity molecular superposition structural alignment 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Silverman, B.D. and Platt, D.E., J. Med. Chem., 39 (1996) 2129.Google Scholar
  2. 2.
    Lemmen, C., Lengauer, T. and Klebe, G., J. Med. Chem., 41 (1998) 4502.Google Scholar
  3. 3.
    Miller, M.D., Sheridan, R.P. and Kearsley, S.K., J. Med. Chem., 42 (1999) 1505.Google Scholar
  4. 4.
    Lemmen, C., Hiller, C. and Lengauer, T., J. Comput. Aid. Mol. Des., 11 (1997) 357.Google Scholar
  5. 5.
    Klebe, G., Mietzner, T. and Weber, F., J. Comput. Aid. Mol. Des., 8 (1994) 751.Google Scholar
  6. 6.
    Kearsley, S.K. and Smith, G.M., J. Comput. Aid. Mol. Des., 8 (1994) 565.Google Scholar
  7. 7.
    McMartin, C. and Bohacek, R.S., J. Med. Chem., 42 (1999) 1505.Google Scholar
  8. 8.
    Handschuh, S., Wagener, M. and Gasteiger, J., J. Chem. Inf. Comput. Sci., 38 (1998) 220.Google Scholar
  9. 9.
    Mestres, J., Rohrer, D.C. and Maggiora, G.M., J. Mol. Graph. Modeling, 15 (1997) 114.Google Scholar
  10. 10.
    Martin Y.C., Bures, M.G., Danaher, E.A., DeLazzer, J., Lico, J. and Pavlik, P.A., J. Comput. Aid. Mol. Des., 7 (1993) 83.Google Scholar
  11. 11.
    Willett, P., J. Mol. Recog., 8 (1995) 290.Google Scholar
  12. 12.
    Jones, G., Willett, P. and Glen, R.C., J. Comput. Aid. Mol. Des., 9 (1995) 532.Google Scholar
  13. 13.
    Thorner, D.A., Wild, D.J., Willett, P. and Wright, P.M., J. Chem. Inform. Comput. Sci., 36 (1996) 900.Google Scholar
  14. 14.
    Wild, D.J. and Willett, P., J. Chem. Inform. Comput. Sci., 36 (1996) 159.Google Scholar
  15. 15.
    Thorner, D.A., Willett, P., Glen, R.C., Wright, P.M. and Taylor, R., J. Comput. Aid. Mol. Des., 1 (1997) 163.Google Scholar
  16. 16.
    Klebe, G., in Kubinyi, H. (ed.), 3D QSAR in Drug Design, ESCOM, Leiden, 1993, pp. 173–199.Google Scholar
  17. 17.
    Kim, K.H., list of comfa references 1993–1997, In Kubinyi, H., Folkers, G. and Martin, Y.C. (eds), 3D QSAR in Drug Design, Vol. 3, Kluwer, Dordrecht, 1998, pp. 317–338.Google Scholar
  18. 18.
    Klebe, G., comparative molecular similarity indicies analysis, in Kubinyi, H., Folkers, G. and Martin, Y.C. (eds), 3D QSAR in Drug Design, Vol. 3. Kluwer, Dordrecht, 1998, pp. 87–104.Google Scholar
  19. 19.
    Good, A.C. and Mason, J.S., three-dimensional structure database searches, in Lipkowitz, K.B. and Boyd, D.B. (eds), Reviews in Computational Chemistry, Vol. 7, chapter 2. VCH Publishers, New York, NY, 1996, pp. 67–117.Google Scholar
  20. 20.
    Kubinyi, H., similarity and dissimilarity: A medicinal chemist's view, in Kubinyi, H., Folkers, G. and Martin, Y.C. (eds), 3D QSAR in Drug Design, Vol. 3. Kluwer, Dordrecht, 1998, pp. 317–338.Google Scholar
  21. 21.
    Klebe, G. and Mietzner, T., J. Comput. Aid. Mol. Des., 8 (1994) 583.Google Scholar
  22. 22.
    Kearsley, S.K., Underwood, D.J., Sheridan, R.P. and Miller, M.D. J. Comput. Aid. Mol. Des., 8 (1994) 565.Google Scholar
  23. 23.
    Hahn, M., J. Chem. Inf. Comput. Sci., 37 (1996) 80.Google Scholar
  24. 24.
    Rarey, M., Kramer, B., Lengauer, T. and Klebe, G., J. Mol. Biol., 261 (1996) 470.Google Scholar
  25. 25.
    Böhm, H.J., J. Comput. Aided. Mol. Des., 6 (1992) 61.Google Scholar
  26. 26.
    Douglas, B.E., McDaniel, D.H. and Alexander, J., Concepts and Models of Inorganic Chemistry. John Wiley & Sons, New York, NY, 1983.Google Scholar
  27. 27.
    Karplus, M. and Porter, R.N., Atoms and Molecules. W. A. Benjamin, Inc., Menlo Park, CA, 1971.Google Scholar
  28. 28.
    Duda, R.O. and Hart, P.E., Pattern Classification and Scene Analysis. John Wiley & Sons, New York, NY, 1973.Google Scholar
  29. 29.
    IBM, Poughkeepsie, NY. Engineering and Scientific Subroutine Library for AIX, Version 3, Guide and Reference, 1997.Google Scholar
  30. 30.
    Stockman, G., Comput. Vision Graphics Image Proc., 40 (1987) 361.Google Scholar
  31. 31.
    NAG Ltd., Oxford, UK, The NAG Fortran Library Manual, Mark 16, 1993.Google Scholar
  32. 32.
    Jain, A.K. and Dubes, R.C., Algorithms for Clustering Data. Prentice Hall, New York, NY, 1988.Google Scholar
  33. 33.
    Curtis, W.D., Janin, A.L. and Zikan, K., a note on averaging rotations, in IEEE Virtual Reality Annual International Symposium, pp. 377–385. IEEE, 1993.Google Scholar
  34. 34.
    Arun, K.S., Huang, T.S. and Blostein, S.D., Least-square fitting of two 3-d point sets. IEEE Transactions on Pattern Analysis and Machine Intelligence, PAMI-9 (5), 1987, pp. 698–700.Google Scholar
  35. 35.
    Carbo, R., Leyda, L. and Arnaua, M., Int. J. Quant. Chem., 17 (1980) 1185.Google Scholar
  36. 36.
    Good, A.C. and Richards, W.G., Explicit calculation of 3d molecular similarity, in Kubinyi, H., Folkers, G. and Martin, Y.C. (eds), 3D QSAR in Drug Design, Vol. (1988) 3664.Google Scholar
  37. 37.
    Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650.Google Scholar
  38. 38.
    Program Cerius2, distributed by Molecular Simulations Inc., 9685 Scranton Rd. San Diego CA 92121–3752.Google Scholar
  39. 39.
    Dunn, W.J. III, Hopfinger, A.J., Cantana, C. and Duraiswami, C., J. Med. Chem., 39 (1996) 4825.Google Scholar
  40. 40.
    Crippen, G.M., J. Med. Chem., 23 (1980) 599.Google Scholar
  41. 41.
    Mayo, S.L., Olafson, B.D. and Goddard III, W.A., J. Phys. Chem., 94 (1990) 8897.Google Scholar
  42. 42.
    Mulliken 2.0: Rice, J.E., Horn, H., Lengsfield III, B.H., McLean, A.D., Carter, J.T., Replogle, E.S., Barnes, L.A., Maluendes, S.A., Lie, G.C., Gutowski, M., Rudge, W.E., Sauer, P.A., Lindh, R., Andersson, K., Chevalier, T.S., Widmark, P.-O., Bouzida, D., Pacansky, J., Singh, K., Gillan, C.J., Carnevali, P., Swope, W.C., Liu, B., IBM Almaden Research Center, San Jose CA, 1996.Google Scholar
  43. 43.
    Lide, D.R., CRC Handbook of Chemistry and Physics, 75th edition, 1994, pp. 9–31.Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Michael C. Pitman
    • 1
  • Wolfgang K. Huber
    • 2
  • Hans Horn
    • 2
  • Andreas Krämer
    • 2
  • Julia E. Rice
    • 2
  • William C. Swope
    • 2
  1. 1.IBM T. J. Watson Research CenterYorktown HeightsUSA
  2. 2.IBM Almaden Research CenterSan Jose

Personalised recommendations